Methods and systems for preventing neuroma formations

ABSTRACT

In some embodiments, a method includes identifying a nerve extending across a transection path; administering a cooling therapy to the identified nerve at a location proximal to the transection path so as to degenerate the identified nerve across the transection path prior to or during surgical transection along the transection path, wherein cooling the identified nerve prevents or reduces neuroma formation at a transected end of the nerve after transection of the nerve. In some embodiments, a method includes degenerating a portion of a nerve while preserving a connective tissue framework of the nerve. During or after the degeneration, the preserved connective tissue framework may be transected at a transection location distal to the treatment location. The regeneration of the nerve may be repeatedly disrupted for a period of time to reduce a regenerative rate of the nerve and delay neuroma formation.

CROSS REFERENCE TO RELATED APPLICATION DATA

The present application is a Continuation of U.S. patent applicationSer. No. 15/069,790 filed Mar. 14, 2016 (Allowed); which claims thebenefit of U.S. Provisional Appln. No. 62/132,238 filed Mar. 12, 2015;the full disclosures which are incorporated herein by reference in theirentirety for all purposes.

BACKGROUND

The present invention generally relates to improved medical devices,systems, and methods. In many embodiments, devices, systems, and methodsfor preventing neuroma formations associated with amputating a limb of apatient are provided.

Amputation is the surgical removal of all or part of a limb or extremitysuch as an arm, leg, foot, hand, toe, or finger. An estimated 1.8million Americans are living with amputations and approximately 185,000amputations occur in the United States each year. Amputation of the leg,either above or below the knee, is the most common amputation surgery.

During an amputation procedure, the portion of nerves extending distallyfrom the amputation level must be transected. Neuroma formation at thetransection site is a natural consequence of the transection and thusamputees may have several neuromas form in their residual limb after theamputation procedure. These neuromas may produce mild discomfort to theamputee or, in more severe cases, may produce continuous and/or severepain. Some prosthetics may be designed such that the socket accommodatesneuromas by avoiding weight bearing or other significant pressure on theneuroma during prosthetic use. While this may be sufficient in someinstances, in others, the neuroma may form at locations, such as bonyprominences, where pressure from use with or without a prosthesis isunavoidable (e.g., metacarpal heads, at the neck of the fibula, etc.).Accordingly, it would be desirable to provide methods and systems forpreventing neuroma formation associated with amputating a limb orextremity of a patient to address such issues as patient discomfortand/or pain. For example, methods and systems which reduce or preventthe formation of neuromas after amputation may be advantageous.

SUMMARY OF THE INVENTION

The present invention generally relates to improved medical devices,systems, and methods. In many embodiments, devices, systems, and methodsfor reducing or preventing the formation of neuromas associated withnerve transection during a medical intervention such as limb amputationor other surgical procedures are provided. The methods and devices maybe beneficial for other exemplary interventions in addition toamputation, such as general thoracic surgeries where surgeons gainaccess between two or more ribs to the chest cavity. Additionally,surgeries involving the heart and major vessels, upper lung, andesophagus may benefit from the methods and devices disclosed herein totherapeutically treat nerves, reduce a regeneration of a nerve, inducechronic denervation, and/or prevent or reduce neuroma formation at atransected end of the nerve.

In many embodiments, improved devices, systems, and methods fortransecting a nerve (e.g., during amputation of a limb or the like) mayprovide chronic denervation of one or more nerves of a patient as partof a therapeutic treatment. The therapeutic treatment may reduce orprevent neuroma formation in at a transected end of the nerve or in aresidual limb of an amputee in the case of an amputation. Theprophylactic methods of the present invention may employ cold therapyfor the prevention of neuromas or fibromas associated with an amputationof a limb of a patient. Embodiments of the invention include cryogeniccooling needles that can be advanced through skin or other tissues tocause axonotmesis of a target nerve of the patient and to repeatedlyinterrupt a regeneration of the nerve so as to provide therapeuticchronic denervation of the target nerve for preventing neuroma formationby a transected or injured nerve. The therapeutic chronic denervationmay prevent the formation of neuromas or fibromas in a residual limb ofthe patient and/or may provide long lasting and permanent pain reliefassociated with the target nerve.

In some embodiments, a method of amputation may be provided. The methodmay prevent neuroma formation in nerve tissue associated with surgicalamputation of a body extremity of a patient. The method may includeidentifying a nerve extending across a cutting path which separates thebody extremity from a body of the patient. A cooling therapy may beadministered to the identified nerve at a location proximal to thecutting path so as to degenerate the identified nerve across the cuttingpath prior to, during, or within a predetermined time period aftersurgically cutting along the cutting path to separate the body extremityfrom the body of the patient and to transect the identified nerve. Thecooling of the identified nerve may prevent or reduce neuroma formationin a residual limb of the patient that remains after amputation.

Optionally, the method may start with the planning of a cutting path atan amputation level to separate the body extremity from a body of thepatient. A nerve extending across the planned cutting path or anamputation level may be identified and a cooling therapy may beadministered to the identified nerve at a location proximal to theplanned cutting path so as to degenerate the identified nerve across thecutting path. After degenerating the identified nerve by administeringthe cooling therapy, the method may include cutting along the plannedcutting path to separate the body extremity from the body of the patientand transecting the identified nerve. The application of cooling therapyprior to, during, or shortly after cutting along the planned cuttingpath may reduce neuroma formation in a residual stump of the patientthat remains after removal of the body extremity of the patient.

The method may further include administering a repeated application ofcooling therapy targeting a regeneration of the identified nerve at oneor more locations proximal to the stump of the patient prior to theregeneration extending to a location of the transection of theidentified nerve. The repeated application may reduce an expression ofnerve growth factors. The repeated application of cooling therapy mayrepeatedly disrupt the regeneration of an axon of the identified nerve.The repeated application of cooling therapy to disrupt the regenerationof the identified nerve may induce chronic denervation of the identifiednerve. The chronic denervation of the identified nerve may reduce aregenerative rate of the identified nerve. In some embodiments, theregenerative rate of the identified nerve may be reduced to less than 1mm per day, to less than 0.5 mm per day, to less than 0.1 mm per day,less than 0.05 mm per day, or permanently disrupted by the chronicdenervation (i.e., approximately 0 mm per day).

In some embodiments, administering the cooling therapy to the nerve mayinclude positioning a needle of a cryotherapy probe across theidentified nerve, aligning visual indicia of the needle of thecryotherapy probe with the nerve (the visual indicial may be indicativeof a treatment area along a length of the needle), and activating thecryotherapy probe to deliver the cooling therapy. The visual indicia maybe a marking identifying a distal end of the treatment area along thelength of the needle. Optionally, the visual indicia may be a markingidentifying a proximal end of the treatment area along the length of theneedle and/or a marking identifying a center of the treatment area alongthe length of the needle. In some embodiments, the length of the needlemay be 10 cm or more. In some embodiments, the cooling therapy may beadministered to the nerve without medical imaging. Administering thecooling therapy to the nerve may be performed by positioning a needle ofa cryotherapy probe along a length of the identified nerve andactivating the cryotherapy probe to deliver the cooling therapy. Theidentified nerve may be a peripheral nerve. The identified nerve may bea sensory nerve.

In some embodiments, the repeated application of cooling therapy may beadministered over a period of one month to three months before or afterthe transection of the nerve. The repeated application of coolingtherapy may be administered between a daily interval and a four weekinterval.

In some embodiments, a cryotherapy probe may be provided. Thecryotherapy probe may include a handle for holding by an operator and aneedle extending distally from the handle. The needle may have aproximal end, a distal end, and a length therebetween. The needle may beconfigured to produce a cooling therapy zone along the length of theneedle when the cryotherapy probe is activated to administer a coolingtherapy. The needle may include at least one visible mark along thelength of the needle to indicate at least one of a distal end, aproximal end, and a center of the cooling therapy zone produced when thecryotherapy probe is activated to administer the cooling therapy.

The needle may include visible marks for each of the distal end, theproximal end, and the center of the cooling therapy zone produced whenthe cryotherapy probe is activated to administer the cooling therapy.The length of the needle may be 10 cm or more. The cryotherapy probeneedle may further include visible marks identifying a distance from thedistal end of the needle.

In further aspects of the present invention, a method of transecting anerve extending to a target tissue is provided. The method may includetreating the nerve by degenerating the nerve at a location along thenerve to degenerate an axon of the nerve while preserving a connectivetissue framework of the nerve. The preserved connective tissue frameworkof the nerve may be transected at a location distal to the locationwhere degeneration was induced. A regeneration of the nerve may berepeatedly disrupted over a period of time so as to induce chronicdenervation of the nerve. The chronic denervation of the nerve mayreduce a regenerative rate of the nerve. The chronic denervation mayprevent neuroma formation at the transection location of the nerve.Optionally, repeatedly disrupting the regeneration of the nervecomprises repeatedly applying cooling therapy to the nerve at a locationproximal to the target tissue. The repeated application of coolingtherapy may be administered over a period of one month to three monthsafter the transection of the nerve. Optionally, the repeated applicationof cooling therapy may be applied between a daily interval and a fourweek interval (e.g., at one week intervals).

The method may further include selecting an interval for the repeatedapplication of cooling therapy based on a distance from the locationwhere degeneration was induced to the target tissue. A shorter intervalmay be selected as the distance decreases and longer intervals may beselected as the distance increases. The repeated application of coolingtherapy may reduce an expression of nerve growth factors. In someembodiments, the repeated application of cooling therapy may reduce aregeneration rate of the nerve.

Other energy based therapies that induce axonotmesis while avoidingdisruption of the connective nervous tissue along the nerve pathway maybe used in the alternative to cooling therapy. Examples of such energybased therapies would include forms of radiofrequency, microwave,ultrasound, laser, etc. Preferably, the energy based therapy inducesaxonotmesis and avoids disrupting the connective nerve tissue.

In any of the embodiments disclosed herein, the one or more needles mayinclude a coating that enhances visibility of the needle in ultrasoundimaging. The coating may be along the entire length of the needle. Insome embodiments, the coating may be only at the at least one visiblemark along the length of the needle. Optionally, the coating may bealong the entire length of the needle except for at the at least onevisible mark along the length of the needle. In some embodiments, thecoating may be along the length of the needle and terminates at thecenter of the cooling therapy zone such that a distal end of the coatingis associated with the center of the cooling therapy zone.

The terms “invention,” “the invention,” “this invention” and “thepresent invention” used in this patent are intended to refer broadly toall of the subject matter of this patent and the patent claims below.Statements containing these terms should be understood not to limit thesubject matter described herein or to limit the meaning or scope of thepatent claims below. Embodiments of the invention covered by this patentare defined by the claims below, not this summary. This summary is ahigh-level overview of various aspects of the invention and introducessome of the concepts that are further described in the DetailedDescription section below. This summary is not intended to identify keyor essential features of the claimed subject matter, nor is it intendedto be used in isolation to determine the scope of the claimed subjectmatter. The subject matter should be understood by reference toappropriate portions of the entire specification of this patent, any orall drawings and each claim.

The invention will be better understood on reading the followingdescription and examining the figures that accompany it. These figuresare provided by way of illustration only and are in no way limiting onthe invention.

BRIEF DESCRIPTION OF THE DRAWINGS

Further details, aspects and embodiments of the invention will bedescribed by way of example only and with reference to the drawings. Inthe drawings, like reference numbers are used to identify like orfunctionally similar elements. Elements in the figures are illustratedfor simplicity and clarity and have not necessarily been drawn to scale.

FIG. 1A is a perspective view of a self-contained subdermal cryogenicprobe and system, according to some embodiments of the invention;

FIG. 1B is a partially transparent perspective view of theself-contained probe of FIG. 1A, showing internal components of thecryogenic system and schematically illustrating replacement treatmentneedles for use with the disposable probe according to some embodimentsof the invention;

FIG. 2A schematically illustrates exemplary components that may beincluded in the treatment system;

FIG. 2B is a cross-sectional view of the system of FIG. 1A, according tosome embodiments of the invention;

FIGS. 2C and 2D are cross-sectional views showing exemplary operationalconfigurations of a portion of the system of FIG. 2B;

FIGS. 3A-3E illustrate exemplary embodiments of needle probes, accordingto some embodiments of the invention;

FIGS. 4A-4C illustrate an exemplary method of introducing a cryogenicprobe to a treatment area, according to some embodiments of theinvention;

FIG. 4D illustrates an alternative exemplary embodiment of a sheath,according to some embodiments of the invention;

FIG. 5 illustrates an exemplary insulated cryoprobe, according to someembodiments of the invention;

FIGS. 6-9 illustrate exemplary embodiments of cryofluid delivery tubes,according to some embodiments of the invention;

FIG. 10 illustrates an example of blunt tipped cryoprobe, according tosome embodiments of the invention;

FIGS. 11 and 12 illustrate exemplary actuatable cryoprobes, according tosome embodiments of the invention;

FIG. 13 is a flow chart illustrating an exemplary algorithm for heatingthe needle probe of FIG. 3A, according to some embodiments of theinvention;

FIG. 14 is a flow chart schematically illustrating an exemplary methodfor treatment using the disposable cryogenic probe and system of FIGS.1A and 1B, according to some embodiments of the invention;

FIG. 15 is a flow chart illustrating an exemplary method for amputatingan extremity of a patient;

FIG. 16 illustrates nerves of the brachial plexus that may be targetedfor treatment according to some embodiments of the present invention;

FIG. 17A and FIG. 17B illustrate nerves of the leg that may be targetedfor treatment according to some embodiments of the present invention;

FIG. 18 illustrates nerve gene expression after nerve injury;

FIGS. 19A-19D illustrate an amputation of a hand of a patient accordingto some embodiments of the invention;

FIGS. 20A-20B illustrate an exemplary system according to someembodiments of the invention; and

FIG. 21 illustrates an exemplary method of treating a nerve according tosome embodiments of the invention.

DETAILED DESCRIPTION

The present invention provides improved medical devices, systems, andmethods. More particularly, the prophylactic methods and devices of thepresent invention may employ cold therapy for the prevention of neuromasor fibromas associated with an amputation of a limb of a patient.Embodiments of the invention may treat target tissues disposed at andbelow the skin, optionally to treat pain associated with a sensorynerve. Embodiments of the invention may utilize a handheld refrigerationsystem that can use a commercially available cartridge of fluidrefrigerant. Refrigerants well suited for use in handheld refrigerationsystems may include nitrous oxide and carbon dioxide. These can achievetemperatures approaching −90° C.

Sensory nerves and associated tissues may be temporarily impaired usingmoderately cold temperatures of 10° C. to −5° C. without permanentlydisabling the tissue structures. Using an approach similar to thatemployed for identifying structures associated with atrial fibrillation,a needle probe or other treatment device can be used to identify atarget tissue structure in a diagnostic mode with these moderatetemperatures, and the same probe (or a different probe) can also be usedto provide a longer term or permanent treatment, optionally by treatingthe target tissue zone and/or inducing apoptosis at temperatures fromabout −5° C. to about −50° C. In some embodiments, apoptosis may beinduced using treatment temperatures from about −1° C. to about −15° C.,or from about −1° C. to about −19° C., optionally so as to provide alonger lasting treatment that limits or avoids inflammation andmobilization of skeletal muscle satellite repair cells. In someembodiments, axonotmesis with Wallerian degeneration of a sensory nerveis desired, which may be induced using treatment temperatures from about−20° C. to about −100° C. Hence, the duration of the treatment efficacyof such subdermal cryogenic treatments may be selected and controlled,with colder temperatures, longer treatment times, and/or larger volumesor selected patterns of target tissue determining the longevity of thetreatment. Additional description of cryogenic cooling methods anddevices may be found in commonly assigned U.S. Pat. No. 7,713,266 (Atty.Docket No. 000110US) entitled “Subdermal Cryogenic Remodeling of Muscle,Nerves, Connective Tissue, and/or Adipose Tissue (Fat)”, U.S. Pat. No.7,850,683 (Atty. Docket No. 000120US) entitled “Subdermal CryogenicRemodeling of Muscles, Nerves, Connective Tissue, and/or Adipose Tissue(Fat)”, U.S. Pat. No. 9,039,688 (Atty. Docket No. 002510US) entitled“Method for Reducing Hyperdynamic Facial Wrinkles”, and U.S. Pat. No.8,298,216 (Atty. Docket No. 000810US) entitled “Pain Management UsingCryogenic Remodeling,” the full disclosures of which are eachincorporated by reference herein.

Referring now to FIGS. 1A and 1B, a system for cryogenic remodeling herecomprises a self-contained probe handpiece generally having a proximalend 12 and a distal end 14. A handpiece body or housing 16 has a sizeand ergonomic shape suitable for being grasped and supported in asurgeon's hand or other system operator. As can be seen most clearly inFIG. 1B, a cryogenic cooling fluid supply 18, a supply valve 32 andelectrical power source 20 are found within housing 16, along with acircuit 22S having a processor for controlling cooling applied byself-contained system 10 in response to actuation of an input 24.Alternatively, electrical power can be applied through a cord from aremote power source. Power source 20 also supplies power to heaterelement 44 in order to heat the proximal region of probe 26 which maythereby help to prevent unwanted skin damage, and a temperature sensor48 adjacent the proximal region of probe 26 helps monitor probetemperature. Additional details on the heater 44 and temperature sensor48 are described in greater detail below. When actuated, supply valve 32controls the flow of cryogenic cooling fluid from fluid supply 18. Someembodiments may, at least in part, be manually activated, such asthrough the use of a manual supply valve and/or the like, so thatprocessors, electrical power supplies, and the like may not be required.

Extending distally from distal end 14 of housing 16 may be atissue-penetrating cryogenic cooling probe 26. Probe 26 is thermallycoupled to a cooling fluid path extending from cooling fluid source 18,with the exemplary probe comprising a tubular body receiving at least aportion of the cooling fluid from the cooling fluid source therein. Theexemplary probe 26 may comprise a 30 G needle having a sharpened distalend that is axially sealed. Probe 26 may have an axial length betweendistal end 14 of housing 16 and the distal end of the needle of betweenabout 0.5 mm and 15 cm. Such needles may comprise a stainless steel tubewith an inner diameter of about 0.006 inches and an outer diameter ofabout 0.012 inches, while alternative probes may comprise structureshaving outer diameters (or other lateral cross-sectional dimensions)from about 0.006 inches to about 0.100 inches. Generally, needle probe26 may comprise a 16 g or smaller size needle, often comprising a 20 gneedle or smaller, typically comprising a 25, 26, 27, 28, 29, or 30 g orsmaller needle.

In some embodiments, probe 26 may comprise two or more needles arrangedin a linear array, such as those disclosed in previously incorporatedU.S. Pat. No. 7,850,683. Another exemplary embodiment of a probe havingmultiple needle probe configurations allow the cryogenic treatment to beapplied to a larger or more specific treatment area. Other needleconfigurations that facilitate controlling the depth of needlepenetration and insulated needle embodiments are disclosed in commonlyassigned U.S. Pat. No. 8,409,185 (Atty. Docket No. 000500US) entitled“Replaceable and/or Easily Removable Needle Systems for Dermal andTransdermal Cryogenic Remodeling,” the entire content of which isincorporated herein by reference. Multiple needle arrays may also bearrayed in alternative configurations such as a triangular or squarearray.

Arrays may be designed to treat a particular region of tissue, or toprovide a uniform treatment within a particular region, or both. In someembodiments needle 26 may be releasably coupled with body 16 so that itmay be replaced after use with a sharper needle (as indicated by thedotted line) or with a needle having a different configuration. Inexemplary embodiments, the needle may be threaded into the body, pressfit into an aperture in the body or have a quick disconnect such as adetent mechanism for engaging the needle with the body. A quickdisconnect with a check valve may be advantageous since it may permitdecoupling of the needle from the body at any time without excessivecoolant discharge. This can be a useful safety feature in the event thatthe device fails in operation (e.g. valve failure), allowing an operatorto disengage the needle and device from a patient's tissue withoutexposing the patient to coolant as the system depressurizes. Thisfeature may also be advantageous because it allows an operator to easilyexchange a dull needle with a sharp needle in the middle of a treatment.One of skill in the art will appreciate that other coupling mechanismsmay be used.

Addressing some of the components within housing 16, the exemplarycooling fluid supply 18 may comprise a canister, sometimes referred toherein as a cartridge, containing a liquid under pressure, with theliquid preferably having a boiling temperature of less than 37° C. atone atmosphere of pressure. When the fluid is thermally coupled to thetissue-penetrating probe 26, and the probe is positioned within thepatient so that an outer surface of the probe is adjacent to a targettissue, the heat from the target tissue evaporates at least a portion ofthe liquid and the enthalpy of vaporization cools the target tissue. Asupply valve 32 may be disposed along the cooling fluid flow pathbetween canister 18 and probe 26, or along the cooling fluid path afterthe probe so as to limit coolant flow thereby regulating thetemperature, treatment time, rate of temperature change, or othercooling characteristics. The valve will often be powered electricallyvia power source 20, per the direction of processor 22, but may at leastin part be manually powered. The exemplary power source 20 comprises arechargeable or single-use battery. Additional details about valve 32are disclosed below and further disclosure on the power source 20 may befound in commonly assigned Int'l Pub. No. WO 2010/075438 (Atty. DocketNo. 002310PC) entitled “Integrated Cryosurgical Probe Package with FluidReservoir and Limited Electrical Power Source,” the entire contents ofwhich are incorporated herein by reference.

The exemplary cooling fluid supply 18 may comprise a single-usecanister. Advantageously, the canister and cooling fluid therein may bestored and/or used at (or even above) room temperature. The canister mayhave a frangible seal or may be refillable, with the exemplary canistercontaining liquid nitrous oxide, N₂O. A variety of alternative coolingfluids might also be used, with exemplary cooling fluids includingfluorocarbon refrigerants and/or carbon dioxide. The quantity of coolingfluid contained by canister 18 will typically be sufficient to treat atleast a significant region of a patient, but will often be less thansufficient to treat two or more patients. An exemplary liquid N₂Ocanister might contain, for example, a quantity in a range from about 1gram to about 40 grams of liquid, more preferably from about 1 gram toabout 35 grams of liquid, and even more preferably from about 7 grams toabout 30 grams of liquid.

Processor 22 will typically comprise a programmable electronicmicroprocessor embodying machine readable computer code or programminginstructions for implementing one or more of the treatment methodsdescribed herein. The microprocessor will typically include or becoupled to a memory (such as a non-volatile memory, a flash memory, aread-only memory (“ROM”), a random access memory (“RAM”), or the like)storing the computer code and data to be used thereby, and/or arecording media (including a magnetic recording media such as a harddisk, a floppy disk, or the like; or an optical recording media such asa CD or DVD) may be provided. Suitable interface devices (such asdigital-to-analog or analog-to-digital converters, or the like) andinput/output devices (such as USB or serial I/O ports, wirelesscommunication cards, graphical display cards, and the like) may also beprovided. A wide variety of commercially available or specializedprocessor structures may be used in different embodiments, and suitableprocessors may make use of a wide variety of combinations of hardwareand/or hardware/software combinations. For example, processor 22 may beintegrated on a single processor board and may run a single program ormay make use of a plurality of boards running a number of differentprogram modules in a wide variety of alternative distributed dataprocessing or code architectures.

Referring now to FIG. 2A, schematic 11 shows a simplified diagram ofcryogenic cooling fluid flow and control. The flow of cryogenic coolingfluid from fluid supply 18 may be controlled by a supply valve 32.Supply valve 32 may comprise an electrically actuated solenoid valve, amotor actuated valve or the like operating in response to controlsignals from controller 22, and/or may comprise a manual valve.Exemplary supply valves may comprise structures suitable for on/offvalve operation, and may provide venting of the fluid source and/or thecooling fluid path downstream of the valve when cooling flow is haltedso as to limit residual cryogenic fluid vaporization and cooling.Additionally, the valve may be actuated by the controller in order tomodulate coolant flow to provide high rates of cooling in some instanceswhere it is desirable to promote necrosis of tissue such as in malignantlesions and the like or slow cooling which promotes ice formationbetween cells rather than within cells when necrosis is not desired.More complex flow modulating valve structures might also be used inother embodiments. For example, other applicable valve embodiments aredisclosed in previously incorporated U.S. Pat. No. 8,409,185.

Still referring to FIG. 2A, an optional heater (not illustrated) may beused to heat cooling fluid supply 18 so that heated cooling fluid flowsthrough valve 32 and through a lumen 34 of a cooling fluid supply tube36. In some embodiments a safety mechanism can be included so that thecooling supply is not overheated. Examples of such embodiments aredisclosed in commonly assigned International Publication No. WO2010075438, the entirety of which is incorporated by reference herein.

Supply tube 36 is, at least in part, disposed within a lumen 38 ofneedle 26, with the supply tube extending distally from a proximal end40 of the needle toward a distal end 42. The exemplary supply tube 36comprises a fused silica tubular structure (not illustrated) having apolymer coating and extending in cantilever into the needle lumen 38.Supply tube 36 may have an inner lumen with an effective inner diameterof less than about 200 μm, the inner diameter often being less thanabout 100 μm, and typically being less than about 40 μm. Exemplaryembodiments of supply tube 36 have inner lumens of between about 15 and50 μm, such as about 30 μm. An outer diameter or size of supply tube 36will typically be less than about 1000 μm, often being less than about800 μm, with exemplary embodiments being between about 60 and 150 μm,such as about 90 μm or 105 μm. The tolerance of the inner lumen diameterof supply tubing 36 will preferably be relatively tight, typically beingabout +/−10 μm or tighter, often being +/−5 μm or tighter, and ideallybeing +/−3 μm or tighter, as the small diameter supply tube may providethe majority of (or even substantially all of) the metering of thecooling fluid flow into needle 26. Additional details on various aspectsof needle 26 along with alternative embodiments and principles ofoperation are disclosed in greater detail in U.S. Pat. No. 9,254,162(Atty. Docket No. 000300US) entitled “Dermal and Transdermal CryogenicMicroprobe Systems and Methods,” the entire contents of which areincorporated herein by reference. Previously incorporated U.S. Pat. No.8,409,185 (Attorney Docket No. 000500US) also discloses additionaldetails on the needle 26 along with various alternative embodiments andprinciples of operation.

The cooling fluid injected into lumen 38 of needle 26 will typicallycomprise liquid, though some gas may also be injected. At least some ofthe liquid vaporizes within needle 26, and the enthalpy of vaporizationcools the needle and also the surrounding tissue engaged by the needle.An optional heater 44 (illustrated in FIG. 1B) may be used to heat theproximal region of the needle in order to prevent unwanted skin damagein this area, as discussed in greater detail below. Controlling apressure of the gas/liquid mixture within needle 26 substantiallycontrols the temperature within lumen 38, and hence the treatmenttemperature range of the tissue. A relatively simple mechanical pressurerelief valve 46 may be used to control the pressure within the lumen ofthe needle, with the exemplary valve comprising a valve body such as aball bearing, urged against a valve seat by a biasing spring. Anexemplary relief valve is disclosed in U.S. Provisional PatentApplication No. 61/116,050 previously incorporated herein by reference.Thus, the relief valve may allow better temperature control in theneedle, minimizing transient temperatures. Further details on exhaustvolume are disclosed in previously incorporated U.S. Pat. No. 8,409,185.

The heater 44 may be thermally coupled to a thermally responsive element50, which is supplied with power by the controller 22 and thermallycoupled to a proximal portion of the needle 26. The thermally responsiveelement 50 can be a block constructed from a material of high thermalconductivity and low heat capacity, such as aluminum. A firsttemperature sensor 52 (e.g., thermistor, thermocouple) can also bethermally coupled the thermally responsive element 50 andcommunicatively coupled to the controller 22. A second temperaturesensor 53 can also be positioned near the heater 44, for example, suchthat the first temperature sensor 52 and second temperature sensor 53are placed in different positions within the thermally responsiveelement 50. In some embodiments, the second temperature sensor 53 isplaced closer to a tissue contacting surface than the first temperaturesensor 52 is placed in order to provide comparative data (e.g.,temperature differential) between the sensors 52, 53. The controller 22can be configured to receive temperature information of the thermallyresponsive element 50 via the temperature sensor 52 in order to providethe heater 44 with enough power to maintain the thermally responsiveelement 50 at a particular temperature.

The controller 22 can be further configured to monitor power draw fromthe heater 44 in order to characterize tissue type, perform devicediagnostics, and/or provide feedback for a tissue treatment algorithm.This can be advantageous over monitoring temperature alone, since powerdraw from the heater 44 can vary greatly while temperature of thethermally responsive element 50 remains relatively stable. For example,during treatment of target tissue, maintaining the thermally responsiveelement 50 at 40° C. during a cooling cycle may take 1.0 W initially(for a needle <10 mm in length) and is normally expected to climb to 1.5W after 20 seconds, due to the needle 26 drawing in surrounding heat. Anindication that the heater is drawing 2.0 W after 20 seconds to maintain40° C. can indicate that an aspect of the system 10 is malfunctioningand/or that the needle 26 is incorrectly positioned. Correlations withpower draw and correlated device and/or tissue conditions can bedetermined experimentally to determine acceptable treatment powerranges.

In some embodiments, it may be preferable to limit frozen tissue that isnot at the treatment temperature, i.e., to limit the size of a formedcooling zone within tissue. Such cooling zones may be associated with aparticular physical reaction, such as the formation of an ice-ball, orwith a particular temperature profile or temperature volume gradientrequired to therapeutically affect the tissue therein. To achieve this,metering coolant flow could maintain a large thermal gradient at itsoutside edges. This may be particularly advantageous in applications forcreating an array of connected cooling zones (i.e., fence) in atreatment zone, as time would be provided for the treatment zone tofully develop within the fenced in portion of the tissue, while theouter boundaries maintained a relatively large thermal gradient due tothe repeated application and removal of refrigeration power. This couldprovide a mechanism within the body of tissue to thermally regulate thetreatment zone and could provide increased ability to modulate thetreatment zone at a prescribed distance from the surface of the skin. Arelated treatment algorithm could be predefined, or it could be inresponse to feedback from the tissue.

Such feedback could be temperature measurements from the needle 26, orthe temperature of the surface of the skin could be measured. However,in many cases monitoring temperature at the needle 26 is impractical dueto size constraints. To overcome this, operating performance of thesensorless needle 26 can be interpolated by measuring characteristics ofthermally coupled elements, such as the thermally responsive element 50.

Additional methods of monitoring cooling and maintaining an unfrozenportion of the needle include the addition of a heating element and/ormonitoring element into the needle itself. This could consist of a smallthermistor or thermocouple, and a wire that could provide resistiveheat. Other power sources could also be applied such as infrared light,radiofrequency heat, and ultrasound. These systems could also be appliedtogether dependent upon the control of the treatment zone desired.

Alternative methods to inhibit excessively low transient temperatures atthe beginning of a refrigeration cycle might be employed instead of ortogether with the limiting of the exhaust volume. For example, thesupply valve 32 might be cycled on and off, typically by controller 22,with a timing sequence that would limit the cooling fluid flowing sothat only vaporized gas reached the needle lumen 38 (or a sufficientlylimited amount of liquid to avoid excessive dropping of the needle lumentemperature). This cycling might be ended once the exhaust volumepressure was sufficient so that the refrigeration temperature would bewithin desired limits during steady state flow. Analytical models thatmay be used to estimate cooling flows are described in greater detail inpreviously incorporated U.S. Pat. No. 9,254,162.

FIG. 2B shows a cross-section of the housing 16. This embodiment of thehousing 16 may be powered by an external source, hence the attachedcable, but could alternatively include a portable power source. Asshown, the housing includes a cartridge holder 50. The cartridge holder50 includes a cartridge receiver 52, which may be configured to hold apressured refrigerant cartridge 18. The cartridge receiver 52 includesan elongated cylindrical passage 54, which is dimensioned to hold acommercially available cooling fluid cartridge 18. A distal portion ofthe cartridge receiver 52 includes a filter device 56, which has anelongated conical shape. In some embodiments, the cartridge holder 50may be largely integrated into the housing 16 as shown, however, inalternative embodiments, the cartridge holder 50 is a wholly separateassembly, which may be pre-provided with a coolant fluid source 18.

The filter device 56 may fluidly couple the coolant fluid source(cartridge) 18 at a proximal end to the valve 32 at a distal end. Thefilter device 56 may include at least one particulate filter 58. In theshown embodiment, a particulate filter 58 at each proximal and distalend of the filter device 56 may be included. The particulate filter 58can be configured to prevent particles of a certain size from passingthrough. For example, the particulate filter 58 can be constructed as amicroscreen having a plurality of passages less than 2 microns in width,and thus particles greater than 2 microns would not be able to pass.

The filter device 56 also includes a molecular filter 60 that isconfigured to capture fluid impurities. In some embodiments, themolecular filter 60 is a plurality of filter media (e.g., pellets,powder, particles) configured to trap molecules of a certain size. Forexample, the filter media can comprise molecular sieves having poresranging from 1-20 Å. In another example, the pores have an average sizeof 5 Å. The molecular filter 60 can have two modalities. In a firstmode, the molecular filter 60 will filter fluid impurities received fromthe cartridge 18. However, in another mode, the molecular filter 60 cancapture impurities within the valve 32 and fluid supply tube 36 when thesystem 10 is not in use, i.e., when the cartridge 18 is not fluidlyconnected to the valve 32.

Alternatively, the filter device 56 can be constructed primarily fromePTFE (such as a GORE material), sintered polyethylene (such as made byPOREX), or metal mesh. The pore size and filter thickness can beoptimized to minimize pressure drop while capturing the majority ofcontaminants. These various materials can be treated to make ithydrophobic (e.g., by a plasma treatment) and/or oleophobic so as torepel water or hydrocarbon contaminants.

It has been found that in some instances fluid impurities may leach outfrom various aspects of the system 10. These impurities can includetrapped moisture in the form of water molecules and chemical gasses. Thepresence of these impurities is believed to hamper cooling performanceof the system 10. The filter device 56 can act as a desiccant thatattracts and traps moisture within the system 10, as well as chemicalsout gassed from various aspects of the system 10. Alternately thevarious aspects of the system 10 can be coated or plated withimpermeable materials such as a metal.

As shown in FIG. 2B and in more detail in FIG. 2C and FIG. 2D, thecartridge 18 can be held by the cartridge receiver 52 such that thecartridge 18 remains intact and unpunctured. In this inactive mode, thecartridge may not be fluidly connected to the valve 32. A removablecartridge cover 62 can be attached to the cartridge receiver 52 suchthat the inactive mode is maintained while the cartridge is held by thesystem 10.

In use, the cartridge cover 62 can be removed and supplied with acartridge containing a cooling fluid. The cartridge cover 62 can then bereattached to the cartridge receiver 52 by turning the cartridge cover62 until female threads 64 of the cartridge cover 62 engage with malethreads of the cartridge receiver 52. The cartridge cover 62 can beturned until resilient force is felt from an elastic seal 66, as shownin FIG. 2C. To place the system 10 into use, the cartridge cover 62 canbe further turned until the distal tip of the cartridge 18 is puncturedby a puncture pin connector 68, as shown in FIG. 2D. Once the cartridge18 is punctured, cooling fluid may escape the cartridge by flowingthrough the filter device 56, where the impurities within the coolingfluid may be captured. The purified cooling fluid then passes to thevalve 32, and onto the coolant supply tube 36 to cool the probe 26. Insome embodiments the filter device, or portions thereof, may bereplaceable.

In some embodiments, the puncture pin connector 68 can have a two-wayvalve (e.g., ball/seat and spring) that is closed unless connected tothe cartridge. Alternately, pressure can be used to open the valve. Thevalve closes when the cartridge is removed. In some embodiments, theremay be a relief valve piloted by a spring which is balanced byhigh-pressure nitrous when the cartridge is installed and the system ispressurized, but allows the high-pressure cryogen to vent when thecryogen is removed. In addition, the design can include a vent port thatvents cold cryogen away from the cartridge port. Cold venting cryogenlocally can cause condensation in the form of liquid water to form fromthe surrounding environment. Liquid water or water vapor entering thesystem can hamper the cryogenic performance. Further, fluid carryingportions of the cartridge receiver 52 can be treated (e.g., plasmatreatment) to become hydrophobic and/or oleophobic so as to repel wateror hydrocarbon contaminants.

Turning now to FIG. 3A and FIG. 3B, an exemplary embodiment of probe 300having multiple needles 302 is described. In FIG. 3A, probe housing 316includes threads 306 that allow the probe to be threadably engaged withthe housing 16 of a cryogenic device. O-rings 308 fluidly seal the probehousing 316 with the device housing 16 and prevent coolant from leakingaround the interface between the two components. Probe 300 includes anarray of three distally extending needle shafts 302, each having asharpened, tissue penetrating tip 304. Using three linearly arrangedneedles allows a greater area of tissue to be treated as compared with asingle needle. In use, coolant flows through lumens 310 into the needleshafts 302 thereby cooling the needle shafts 302. Ideally, only thedistal portion of the needle shaft 302 would be cooled so that only thetarget tissue receives the cryogenic treatment. However, as the coolingfluid flows through the probe 300, probe temperature decreasesproximally along the length of the needle shafts 302 towards the probehub 318. The proximal portion of needle shaft 302 and the probe hub 318contact skin and may become very cold (e.g. −20° C. to −25° C.) and thiscan damage the skin in the form of blistering or loss of skinpigmentation. Therefore it would be desirable to ensure that theproximal portion of needle shaft 302 and hub 318 remains warmer than thedistal portion of needle shaft 302. A proposed solution to thischallenge is to include a heater element 314 that can heat the proximalportion of needle shaft 302 and an optional temperature sensor 312 tomonitor temperature in this region. To further this, a proximal portionof the needle shaft 302 can be coated with a highly thermally conductivematerial, e.g., gold, that is conductively coupled to both the needleshaft 302 and heater element 314. Details of this construction aredisclosed below.

In the exemplary embodiment of FIG. 3A, resistive heater element 314 isdisposed near the needle hub 318 and near a proximal region of needleshaft 302. The resistance of the heater element is preferably 1Ω to 1KΩ,and more preferably from 5Ω to 50Ω. Additionally, a temperature sensor312 such as a thermistor or thermocouple is also disposed in the samevicinity. Thus, during a treatment as the needles cool down, the heater314 may be turned on in order to heat the hub 318 and proximal region ofneedle shaft 302, thereby preventing this portion of the device fromcooling down as much as the remainder of the needle shaft 302. Thetemperature sensor 312 may provide feedback to controller 22 and afeedback loop can be used to control the heater 314. The cooling powerof the nitrous oxide may eventually overcome the effects of the heater,therefore the microprocessor may also be programmed with a warning lightand/or an automatic shutoff time to stop the cooling treatment beforeskin damage occurs. An added benefit of using such a heater element isthe fact that the heat helps to moderate the flow of cooling fluid intothe needle shaft 302 helping to provide more uniform coolant mass flowto the needles shaft 302 with more uniform cooling resulting.

The embodiment of FIG. 3A illustrates a heater fixed to the probe hub.In other embodiments, the heater may float, thereby ensuring proper skincontact and proper heat transfer to the skin. Examples of floatingheaters are disclosed in commonly assigned Int'l Pub. No. WO 2010/075448(Atty. Docket No. 002310PC) entitled “Skin Protection for SubdermalCryogenic Remodeling for Cosmetic and Other Treatments,” the entirety ofwhich is incorporated by reference herein.

In this exemplary embodiment, three needles are illustrated. One ofskill in the art will appreciate that a single needle may be used, aswell as two, four, five, six, or more needles may be used. When aplurality of needles are used, they may be arranged in any number ofpatterns. For example, a single linear array may be used, or a twodimensional or three dimensional array may be used. Examples of twodimensional arrays include any number of rows and columns of needles(e.g. a rectangular array, a square array, elliptical, circular,triangular, etc.), and examples of three dimensional arrays includethose where the needle tips are at different distances from the probehub, such as in an inverted pyramid shape.

FIG. 3B illustrates a cross-section of the needle shaft 302 of needleprobe 300. The needle shaft can be conductively coupled (e.g., welded,conductively bonded, press fit) to a conductive heater 314 to enableheat transfer therebetween. The needle shaft 302 is generally a small(e.g., 20-30 gauge) closed tip hollow needle, which can be between about0.2 mm and 15 cm, preferably having a length from about 0.3 cm to about3 cm. The conductive heater element 314 can be housed within aconductive block 315 of high thermally conductive material, such asaluminum and include an electrically insulated coating, such as Type IIIanodized coating to electrically insulate it without diminishing itsheat transfer properties. The conductive block 315 can be heated by aresister or other heating element (e.g. cartridge heater, nichrome wire,etc.) bonded thereto with a heat conductive adhesive, such as epoxy. Athermistor can be coupled to the conductive block 315 with heatconductive epoxy allows temperature monitoring. Other temperaturesensors may also be used, such as a thermocouple.

A cladding 320 of conductive material is directly conductively coupledto the proximal portion of the shaft of the needle 302, which can bestainless steel. In some embodiments, the cladding 320 is a layer ofgold, or alloys thereof, coated on the exterior of the proximal portionof the needle shaft 302. In some embodiments, the exposed length ofcladding 320 on the proximal portion of the needle is 2-100 mm. In someembodiments, the cladding 320 can be of a thickness such that the cladportion has a diameter ranging from 0.017-0.020 in., and in someembodiments 0.0182 in. Accordingly, the cladding 320 can be conductivelycoupled to the material of the needle 302, which can be less conductive,than the cladding 320. The cladding 320 may modify the lateral forcerequired to deflect or bend the needle 26. Cladding 320 may be used toprovide a stiffer needle shaft along the proximal end in order to moreeasily transfer force to the leading tip during placement and allow thedistal portion of the needle to deflect more easily when it isdissecting a tissue interface within the body. The stiffness of needle26 can vary from one end to the other end by other means such asmaterial selection, metal tempering, variation of the inner diameter ofthe needle 26, or segments of needle shaft joined together end-to-end toform one contiguous needle 26. In some embodiments, increasing thestiffness of the distal portion of the needle 26 can be used to flex theproximal portion of the needle to access difficult treatment sites as inthe case of upper limb spasticity where bending of the needle outsidethe body may be used to access a target peripheral nerve along thedesired tissue plane.

In some embodiments, the cladding 320 can include sub-coatings (e.g.,nickel) that promote adhesion of an outer coating that would otherwisenot bond well to the needle shaft 302. Other highly conductive materialscan be used as well, such as copper, silver, aluminum, and alloysthereof. In some embodiments, a protective polymer or metal coating cancover the cladding to promote biocompatibility of an otherwisenon-biocompatible but highly conductive cladding material. Such abiocompatible coating however, would be applied to not disruptconductivity between the conductive block 315. In some embodiments, aninsulating layer, such as a ceramic material, is coated over thecladding 320, which remains conductively coupled to the needle shaft302.

In use, the cladding 320 can transfer heat to the proximal portion ofthe needle 302 to prevent directly surrounding tissue from dropping tocryogenic temperatures. Protection can be derived from heating thenon-targeting tissue during a cooling procedure, and in some embodimentsbefore the procedure as well. The mechanism of protection may beproviding heat to pressurized cryogenic cooling fluid passing within theproximal portion of the needle to affect complete vaporization of thefluid. Thus, the non-target tissue in contact with the proximal portionof the needle shaft 302 does not need to supply heat, as opposed totarget tissue in contact with the distal region of the needle shaft 302.To help further this effect, in some embodiments the cladding 320 iscoating within the interior of the distal portion of the needle, with orwithout an exterior cladding. To additionally help further this effect,in some embodiments, the distal portion of the needle can be thermallyisolated from the proximal portion by a junction, such as a ceramicjunction. While in some further embodiments, the entirety of theproximal portion is constructed from a more conductive material than thedistal portion.

In use, it has been determined experimentally that the cladding 320 canhelp limit formation of a cooling zone to the distal portion of theneedle shaft 302, which tends to demarcate at a distal end of thecladding 320. Accordingly, cooling zones are formed only about thedistal portions of the needles. Thus, non-target tissue in directcontact with proximal needle shafts remain protected from effects ofcryogenic temperatures. Such effects can include discoloration andblistering of the skin. Such cooling zones may be associated with aparticular physical reaction, such as the formation of an ice-ball, orwith a particular temperature required to therapeutically affect thetissue therein.

Standard stainless steel needles and gold clad steel needles were testedin porcine muscle and fat. Temperatures were recorded measured 2 mm fromthe proximal end of the needle shafts, about where the cladding distallyterminates, and at the distal tip of the needles. Temperatures for cladneedles were dramatically warmer at the 2 mm point versus the uncladneedles, and did not drop below 4° C. The 2 mm points of the standardstainless steel needles almost equalize in temperature with the distaltip at temperatures below 0° C.

FIGS. 3C and 3D illustrates a detachable probe tip 322 having a hubconnector 324 and an elongated probe 326. The probe tip 322 shares muchof its construction with probe 300. However, the elongated probe 326features a blunt tip 328 that is adapted for blunt dissection of tissue.The blunt tip 328 can feature a full radius tip, less than a full radiustip, or conical tip. In some embodiments, a dulled or truncated needleis used. The elongated probe 326 can be 20 gauge or smaller in diameter,and in some embodiments range in size from 25-30 gauge. As with theembodiments described above, an internal supply tube 330 extends incantilever. However, the exit of the supply tube 330 can be disposed atpositions within the elongated probe 326 other than proximate the blunttip 328. Further, the supply tube 330 can be adapted to create anelongated zone of cooling, e.g., by having multiple exit points forcryofluid to exit from.

The elongated probe 326 and supply tube 330 may be configured toresiliently bend in use, throughout their length at angles approaching120°, with a 5-10 mm bend radius. This may be very challengingconsidering the small sizes of the elongated probe 326 and supply tube330, and also considering that the supply tube 330 is often constructedfrom fused silica. Accordingly, the elongated probe 326 can beconstructed from a resilient material, such as stainless steel, and of aparticular diameter and wall thickness [0.004 to 1.0 mm], such that theelongated probe in combination with the supply tube 330 is not overlyresilient so as to overtly resist manipulation, but sufficiently strongso as to prevent kinking that can result in coolant escaping. Forexample, the elongated probe can be 15 gauge or smaller in diameter,even ranging from 20-30 gauge in diameter. The elongated probe can havea very disparate length to diameter ratio, for example, the elongatedprobe can be greater than 30 mm in length, and in some cases range from30-100 mm in length. To further the aforementioned goals, the supplytube 330 can include a polymer coating 332, such as a polyimide coatingthat terminates approximately halfway down its length, to resist kinkingand aid in resiliency. The polymer coating 332 can be a secondarycoating over a primary polyimide coating that extends fully along thesupply tube. However, it should be understood that the coating is notlimited to polyimide, and other suitable materials can be used. In someembodiments, the flexibility of the elongated probe 326 will vary fromthe proximal end to the distal end. For example, by creating certainportions that have more or less flexibility than others. This may bedone, for example, by modifying wall thickness, adding material (such asthe cladding discussed above), and/or heat treating certain portions ofthe elongated probe 326 and/or supply tube 330. For example, decreasingthe flexibility of elongated probe 326 along the proximal end canimprove the transfer of force from the hand piece to the elongated probeend for better feel and easier tip placement for treatment. Theelongated probe and supply line 330 are may be configured to resilientlybend in use to different degrees along the length at angles approaching120°, with a varying bend radius as small as 5 mm. In some embodiments,the elongated probe 326 will have external markings along the needleshaft indicating the length of needle inserted into the tissue.

FIG. 3E illustrates an exemplary detachable probe tip 322 insertedthrough skin surface SS. As illustrated, the probe tip 322 is insertedalong an insertion axis IA through the skin surface SS. Thereafter, theneedle may be bent away from the insertion axis IA and advanced toward atarget tissue TT in order to position blunt tip 328 adjacent to thetarget tissue TT. In some embodiments, the target tissue may be theinfrapatellar branch of the saphenous nerve. In other embodiments thetarget tissue may be one or more branches of the anterior femoralcutaneous nerve or the lateral femoral cutaneous nerve.

In some embodiments, the probe tip 322 does not include a heatingelement, such as the heater described with reference to probe 300, sincethe effective treating portion of the elongated probe 326 (i.e., thearea of the elongated probe where a cooling zone emanates from) is welllaterally displaced from the hub connector 324 and elongated probeproximal junction. Embodiments of the supply tube are further describedbelow and within commonly assigned U.S. Pub. No. 2012/0089211, which isincorporated by reference.

FIGS. 4A-4C illustrate an exemplary method of creating a hole throughthe skin that allows multiple insertions and positioning of a cryoprobetherethrough. This may be helpful when the needle must be advanceddistally past dense scar tissue. In FIG. 4A a cannula or sheath 1902 isdisposed over a needle 1904 having a tissue penetrating distal end 1908.The cannula may have a tapered distal portion 1906 to help spread anddilate the skin during insertion. The needle/sheath assembly is thenadvanced into and pierces the skin 1910 into the desired target tissue1912. The inner pathway of the cannula or sheath 1902 may be curved toassist in directing the flexible needle 1904, or other probe, into adesired tissue layer coincident with the desired needle path in thetissue. Once the needle/sheath assembly has been advanced to a desiredlocation, the needle 1904 may be proximally retracted and removed fromthe sheath 1902. The sheath (or introducer) now may be used as an easyway of introducing a cryoprobe through the skin without piercing it, anddirecting the cryoprobe to the desired target treatment area. FIG. 4Bshows the sheath 1902 in position with the needle 1904 removed. FIG. 4Cshows insertion of a cryoprobe 1914 into the sheath such that a blunttip 1916 of the cryoprobe 1914 is adjacent the target treatment tissue.The cryoprobe may then be cooled and the treatment tissue cooled toachieve any of the cosmetic or therapeutic effects discussed above. Inthis embodiment, the cryoprobe preferably has a blunt tip 1916 in orderto minimize tissue trauma. In other embodiments, the tip may be sharpand be adapted to penetrate tissue, or it may be round and spherical.The cryoprobe 1914 may then be at least partially retracted from thesheath 1902 and/or rotated and then re-advanced to the same or differentdepth and repositioned in sheath 1902 so that the tip engages adifferent portion of the target treatment tissue without requiring anadditional piercing of the skin. The probe angle relative to the tissuemay also be adjusted, and the cryoprobe may be advanced and retractedmultiple times through the sheath so that the entire target tissue iscryogenically treated.

While the embodiment of FIGS. 4A-4C illustrates a cryoprobe having onlya single probe, the cryoprobe may have an array of probes. Any of thecryoprobes described above may be used with an appropriately sizedsheath. In some embodiments, the cryoprobe comprises a linear or twodimensional array of probes. Lidocaine or other local anesthetics may beused during insertion of the sheath or cryoprobe in order to minimizepatient discomfort. The angle of insertion for the sheath may beanywhere from 0 to 180 degrees relative to the skin surface, and inspecific embodiments is 15 to 45 degrees. The sheath may be inserted atany depth, but in specific embodiments of treating lines/wrinkles of theface, the sheath may be inserted to a depth of 1 mm to 10 mm, and morepreferably to a depth of 2 mm to 5 mm.

In an alternative embodiment seen in FIG. 4D, the sheath 1902 mayinclude an annular flange 1902 b on an outside surface of the sheath inorder to serve as a stop so that the sheath is only inserted a presetamount into the tissue. The position of the flange 1902 b may beadjustable or fixed. The proximal end of the sheath in this embodiment,or any of the other sheath embodiments may also include a one way valvesuch as a hemostasis valve to prevent backflow of blood or other fluidsthat may exit the sheath. The sheath may also insulate a portion of thecryoprobe and prevent or minimize cooling of unwanted regions of tissue.

Any of the cryoprobes described above may be used with the sheathembodiment described above (e.g. in FIGS. 3B, 4A-4C). Other cryoprobesmay also be used with this sheath embodiment, or they may be used alone,in multi-probe arrays, or combined with other treatments. For example, aportion of the cryoprobe 2006 may be insulated as seen in FIG. 5.Cryoprobe 2006 includes a blunt tip 2004 with an insulated section 2008of the probe. Thus, when the cryoprobe is disposed in the treatmenttissue under the skin 2002 and cooled, the cryoprobe preferentiallycreates a cooling zone along one side while the other side remainsuncooled, or only experiences limited cooling. For example, in FIG. 5,the cooling zone 2010 is limited to a region below the cryoprobe 2006,while the region above the cryoprobe and below the skin 2002 remainunaffected by the cooling.

Different zones of cryotherapy may also be created by differentgeometries of the coolant fluid supply tube that is disposed in thecryoprobe. FIGS. 6-9 illustrate exemplary embodiments of differentcoolant fluid supply tubes. In FIG. 6 the coolant fluid supply tube 2106is offset from the central axis of a cryoprobe 2102 having a blunt tip2104. Additionally, the coolant fluid supply tube 2106 includes severalexit ports for the coolant including circular ports 2110, 2112 near thedistal end of the coolant fluid supply tube and an elliptical port 2108proximal of the other ports. These ports may be arranged in varyingsizes, and varying geometries in order to control the flow of cryofluidwhich in turn controls probe cooling of the target tissue. FIG. 7illustrates an alternative embodiment of a coolant fluid supply tube2202 having a plurality of circular ports 2204 for controlling cryofluidflow. FIG. 8 illustrates yet another embodiment of a coolant fluidsupply tube 2302 having a plurality of elliptical holes 2304, and FIG. 9shows still another embodiment of a coolant fluid supply tube 2402having a plurality of ports ranging from smaller diameter circular holes2404 near the distal end of the supply tube 2402 to larger diametercircular holes 2406 that are more proximally located on the supply tube2402.

As discussed above, it may be preferable to have a blunt tip on thedistal end of the cryoprobe in order to minimize tissue trauma. Theblunt tip may be formed by rounding off the distal end of the probe, ora bladder or balloon 2506 may be placed on the distal portion of theprobe 2504 as seen in FIG. 10. A filling tube or inflation lumen 2502may be integral with or separate from the cryoprobe 2504, and may beused to deliver fluid to the balloon to fill the balloon 2506 up to formthe atraumatic tip.

In some instances, it may be desirable to provide expandable cryoprobesthat can treat different target tissues or accommodate differentanatomies. For example, in FIGS. 11 and 12, a pair of cryoprobes 2606with blunt tips 2604 may be delivered in parallel with one another andin a low profile through a sheath 2602 to the treatment area. Oncedelivered, the probes may be actuated to separate the tips 2604 from oneanother, thereby increasing the cooling zone. After the cryotherapy hasbeen administered, the probes may be collapsed back into their lowprofile configuration, and retracted from the sheath.

In some embodiments, the probe may have a sharp tissue piercing distaltip, and in other embodiments, the probe may have a blunt tip forminimizing tissue trauma. To navigate through tissue, it may bedesirable to have a certain column strength for the probe in order toavoid bending, buckling or splaying, especially when the probe comprisestwo or more probes in an array. One exemplary embodiment may utilize avariable stiff portion of a sleeve along the probe body to provideadditional column strength for pushing the probe through tissue.

An exemplary algorithm 400 for controlling the heater element 314, andthus for transferring heat to the cladding 320, is illustrated in FIG.13. In FIG. 13, the start of the interrupt service routine (ISR) 402begins with reading the current needle hub temperature 404 using atemperature sensor such as a thermistor or thermocouple disposed nearthe needle hub. The time of the measurement is also recorded. This datais fed back to controller 22 where the slope of a line connecting twopoints is calculated. The first point in the line is defined by thecurrent needle hub temperature and time of its measurement and thesecond point consists of a previous needle hub temperature measurementand its time of measurement. Once the slope of the needle hubtemperature curve has been calculated 406, it is also stored 408 alongwith the time and temperature data. The needle hub temperature slope isthen compared with a slope threshold value 410. If the needle hubtemperature slope is less than the threshold value then a treating flagis activated 412 and the treatment start time is noted and stored 414.If the needle hub slope is greater than or equal to the slope thresholdvalue 410, an optional secondary check 416 may be used to verify thatcooling has not been initiated. In step 416, absolute needle hubtemperature is compared to a temperature threshold. If the hubtemperature is less than the temperature threshold, then the treatingflag is activated 412 and the treatment start time is recorded 414 aspreviously described. As an alternative, the shape of the slope could becompared to a norm, and an error flag could be activated for an out ofnorm condition. Such a condition could indicate the system was notheating or cooling sufficiently. The error flag could trigger anautomatic stop to the treatment with an error indicator light.Identifying the potential error condition and possibly stopping thetreatment may prevent damage to the proximal tissue in the form of toomuch heat, or too much cooling to the tissue. The algorithm preferablyuses the slope comparison as the trigger to activate the treatment flagbecause it is more sensitive to cooling conditions when the cryogenicdevice is being used rather than simply measuring absolute temperature.For example, a needle probe exposed to a cold environment wouldgradually cool the needle down and this could trigger the heater to turnon even though no cryogenic cooling treatment was being conducted. Theslope more accurately captures rapid decreases in needle temperature asare typically seen during cryogenic treatments.

When the treatment flag is activated 418 the needle heater is enabled420 and heater power may be adjusted based on the elapsed treatment timeand current needle hub temperature 422. Thus, if more heat is required,power is increased and if less heat is required, power is decreased.Whether the treatment flag is activated or not, as an additional safetymechanism, treatment duration may be used to control the heater element424. As mentioned above, eventually, cryogenic cooling of the needlewill overcome the effects of the heater element. In that case, it wouldbe desirable to discontinue the cooling treatment so that the proximalregion of the probe does not become too cold and cause skin damage.Therefore, treatment duration is compared to a duration threshold valuein step 424. If treatment duration exceeds the duration threshold thenthe treatment flag is cleared or deactivated 426 and the needle heateris deactivated 428. If the duration has not exceeded the durationthreshold 424 then the interrupt service routine ends 430. The algorithmthen begins again from the start step 402. This process continues aslong as the cryogenic device is turned on.

Preferred ranges for the slope threshold value may range from about −5°C. per second to about −90° C. per second and more preferably range fromabout −30° C. per second to about −57° C. per second. Preferred rangesfor the temperature threshold value may range from about 15° C. to about0° C., and more preferably may range from about 0° C. to about 10° C.Treatment duration threshold may range from about 15 seconds to about 75seconds.

It should be appreciated that the specific steps illustrated in FIG. 13provide a particular method of heating a cryogenic probe, according toan embodiment of the present invention. Other sequences of steps mayalso be performed according to alternative embodiments. For example,alternative embodiments of the present invention may perform the stepsoutlined above in a different order. Moreover, the individual stepsillustrated in FIG. 13 may include multiple sub-steps that may beperformed in various sequences as appropriate to the individual step.Furthermore, additional steps may be added or removed depending on theparticular applications.

The heating algorithm may be combined with a method for treating apatient. Referring now to FIG. 14, a method 100 facilitates treating apatient using a cryogenic cooling system having a reusable or disposablehandpiece either of which that can be self-contained or externallypowered with replaceable needles such as those of FIG. 1B and a limitedcapacity battery or metered electrical supply. Method 100 generallybegins with a determination 110 of the desired tissue therapy andresults, such as the inhibition of pain from a particular site.Appropriate target tissues for treatment are identified 112 (a tissuethat transmits the pain signal), allowing a target treatment depth,target treatment temperature profile, or the like to be determined. Step112 may include performing a tissue characterization and/or devicediagnostic algorithm, based on power draw of system 10, for example.

The application of the treatment algorithm 114 may include the controlof multiple parameters such as temperature, time, cycling, pulsing, andramp rates for cooling or thawing of treatment areas. In parallel withthe treatment algorithm 114, one or more power monitoring algorithms 115can be implemented. An appropriate needle assembly can then be mounted116 to the handpiece, with the needle assembly optionally having aneedle length, skin surface cooling chamber, needle array, and/or othercomponents suitable for treatment of the target tissues. Simpler systemsmay include only a single needle type, and/or a first needle assemblymounted to the handpiece.

Pressure, heating, cooling, or combinations thereof may be applied 118to the skin surface adjacent the needle insertion site before, during,and/or after insertion 120 and cryogenic cooling 122 of the needle andassociated target tissue. Non-target tissue directly above the targettissue can be protected by directly conducting energy in the form ofheat to the cladding on a proximal portion of the needle shaft duringcooling. Upon completion of the cryogenic cooling cycle the needles willneed additional “thaw” time 123 to thaw from the internally createdcooling zone to allow for safe removal of the probe without physicaldisruption of the target tissues, which may include, but not be limitedto nerves, muscles, blood vessels, or connective tissues. This thaw timecan either be timed with the refrigerant valve shut-off for as short atime as possible, preferably under 15 seconds, more preferably under 5seconds, manually or programmed into the controller to automaticallyshut-off the valve and then pause for a chosen time interval until thereis an audible or visual notification of treatment completion.

Heating of the needle may be used to prevent unwanted skin damage usingthe apparatus and methods previously described. The needle can then beretracted 124 from the target tissue. If the treatment is not complete126 and the needle is not yet dull 128, pressure and/or cooling can beapplied to the next needle insertion location site 118, and theadditional target tissue treated. However, as small gauge needles maydull after being inserted only a few times into the skin, any needlesthat are dulled (or otherwise determined to be sufficiently used towarrant replacement, regardless of whether it is after a singleinsertion, 5 insertions, or the like) during the treatment may bereplaced with a new needle 116 before the next application ofpressure/cooling 118, needle insertion 120, and/or the like. Once thetarget tissues have been completely treated, or once the cooling supplycanister included in the self-contained handpiece is depleted, the usedcanister and/or needles can be disposed of 130. The handpiece mayoptionally be discarded.

In some embodiments of the present invention, a method of amputating anextremity of a patient is provided. Optionally, embodiments of thecryogenic cooling devices described above may be utilized in theamputation method described below.

FIG. 15 illustrates an exemplary method 600 for amputating an extremityof a patient. The method 600 may start by identifying the extremity ofthe patient to be amputated 602. After identifying the extremity of thepatient to be amputated, an amputation level for the type of amputationmay be identified or a cutting path may be planned 604 to separate theidentified extremity from the body of the patient. A nerve extendingacross the amputation level or planned cutting path may be identified606. Axonotmesis of the nerve may be induced 608 at a location proximalto the amputation level or planned cutting path. The identified nervemay degenerate across the amputation level or cutting path 610. Theidentified extremity may be separated from the body of the patient bycutting along the amputation level or planned cutting path 612. Afteramputation of the extremity, a regeneration of the identified nerve maybe interrupted 614. The interruption of the regeneration of theidentified nerve may induce chronic denervation of the identified nerve616. A regenerative rate/capacity of the identified nerve 618 may bereduced. The identified nerve may be prevented from forming a neuroma atthe residual stump of the patient 620.

The method 600 may be applicable to many body extremities that are to beamputated. Amputation surgery may be necessary if an injured or diseasedlimb is not expected to heal and if the patient's life is endangered asa result. Possible causes include circulation issues, infections,accidents, cancer, or a congenital malformation of the limb. In thesecases, it is usually known well in advance that an amputation willbecome necessary. In contrast, sometimes it is necessary to amputateunexpectedly, for example due to a severe injury after an accident. Themethod 600 may be applicable to upper limb amputations: metacarpalamputation, wrist disarticulation, transradial amputation, elbowdisarticulation, transhumeral amputation, shoulder disarticulation,forequarter amputation etc. Additionally, method 600 may be applicableto lower limb amputations: foot amputation, transtibial amputation, kneedisarticulation, transfemoral amputation, hip disarticulation,hemipelvectomy, etc. The method 600 may also be carried out, as desiredor needed, for the amputation of other portions of the body.

After identifying the extremity to be amputated 602, an amputation levelmay be determined and/or a cutting path may be planned 604 to separatethe identified extremity from the body of the patient. The termamputation level may be used to describe the location at which the bodypart is amputated. The amputation level may be determined by the doctorbefore the operation and is based on the reason for the amputation. Forplanned interventions, a prosthetist may be consulted as well in orderto identify which amputation level is suitable for subsequent fitting ofthe prosthesis. A cutting path may be planned based on the identifiedamputation level. For example, for a lower limb amputation, atransfemoral amputation may be prescribed 604 and an associated cuttingpath may be planned 604 that traverses the femur at an preferred height.

After identifying the type and level of amputation and/or planning anassociated cutting path 604, one or more nerves extending across theamputation level or planned cutting path may be identified 606. Forexample, for an upper limb transradial amputation, one or more of thenerves of the brachial plexus, FIG. 16, may be identified for treatmentsuch as the medial cutaneous nerve of the forearm, the ulnar nerve,radial nerve, the median nerve, etc. For a lower limb transtibial ortransfemoral amputation, one or more nerves of leg, FIG. 17A-FIG. 17B,may be identified for treatment such as the sciatic nerve, tibial nerve,common peroneal nerve, superficial peroneal nerve, deep peroneal nerve,sural nerve, lateral cutaneous nerve of the calf, saphenous nerve,femoral nerve, etc.

After identifying one or more nerves extending across the identifiedamputation level or planned cutting path 606, axonotmesis of the nervemay be induced 608 at a location proximal to the amputation level orplanned cutting path. Axonotmesis is a type of nerve injury thatinvolves the loss of relative continuity of the axon and its coveringmyelin sheath but preservation of the connective tissue framework of thenerve at the treatment site and distal to the treatment site. Thus theaxon and myelin sheath may be disrupted or otherwise damaged, but theendoneurium, perineurium, and epineurium may remain intact. This type ofnerve damage may result in the loss of function of the nerve (motor orsensory) distal to the site of injury. Due to the loss in continuity ofthe axon, Wallerian degeneration may occur where the cell body of thenerve degenerates distal to the site of injury. After injury, the distalaxonal skeleton disintegrates, and the axonal membrane breaks apart. Theaxonal degeneration is followed by degradation of the myelin sheath andinfiltration by macrophages. The macrophages, accompanied by Schwanncells, serve to clear the debris from the degeneration. In manyembodiments, the axonotmesis may be induced 608 using embodiments of thecryogenic cooling probes described above. Axonotmesis may be inducedwith interventions such as cryogenic cooling therapy. Alternatively,thermal ablation therapies that operate under controlled temperaturesmay be used to induce axonotmesis (e.g. radiofrequency, microwave,laser, ultrasound) while avoiding an irreversible nerve injury involvinga disruption of connective nerve tissue. By disrupting the connectivetissue of the nerve at the proximal point of treatment, an ablativetreatment may have a lower incidence of neuroma formation with potentialchronic pain resulting from the neuroma formation.

Thus, according to method 600, due to the axonotmesis at a locationproximal to the amputation level or planned cutting path, the identifiednerve may degenerate across the amputation level or cutting path 610 anddistally from the amputation level or cutting path. Thereafter, theidentified extremity may be separated from the body of the patient bycutting along the amputation level or planned cutting path 612. Theamputation may proceed using known methods for removing and reformingtissue and dressing the wound. The amputation of the extremity transectsthe identified nerve at a transection location/site. After inducingaxonotmesis, a proximal portion of the identified nerve that remains maysprout in a distal direction as part of the nerve's healing process. Inmany embodiments, the amputation 612 occurs prior to the regeneration ofthe identified nerve across the amputation level or planned cuttingpath. In such a method, only the connective tissue of the identifiednerve is transected whereas the axon has already experienceddegeneration across the amputation level or planned cutting path priorto amputation.

While method 600 is generally discussed as inducing axonotmesis prior toamputation, it should be understood that in other embodiments, theaxonotmesis may be induced concurrently with the amputation of theextremity or shortly thereafter. If axonotmesis is induced afteramputation, it may be beneficial to induce axonotmesis proximal to thesite of nerve transection within a month after amputation (e.g., withina couple weeks, a week, or a day after amputation) such that neuromaformation by the transected nerve at the transection site may beprevented.

During the regenerative process of the nerve, the nerve may continue toregenerate along the nerve's remaining connective tissue in a distaldirection from the site of injury (where the axonotmesis is induced) ata rate of about 1 mm to 2 mm per day. In some embodiments of the presentinvention, it may be beneficial, but not necessary, to interrupt theregeneration of the identified nerve 614. The reinnervation of thedistal connective tissue of the identified nerve may be interrupted byre-inducing axonotmesis at a site proximal to the distal end of theregenerating nerve. For example, in some embodiments, the cryogeniccooling probes described above may be used to re-induce axonotmesis ofthe identified nerve. Optionally, a cooling treatment may beadministered at about the site of the initial axonotmesis of theidentified nerve. The interruption of the nerve's regeneration may occurover regular intervals for a period of time. For example, in someembodiments, the regeneration of the identified nerve may be interruptedanywhere from daily to as long as 4 week intervals (e.g., weeklyintervals, biweekly intervals, etc.). Further, the regeneration may beinterrupted over a period from 1 month to as long as 6 months (e.g.,repeated treatments over 3 months). In some embodiments, interruption ofthe regeneration of the nerve may be provided by follow on repeattreatments. The repeat treatments prevent regeneration of the nerve atthe transection site of the nerve. It should be understood that eachrepeat treatment does not need to occur at the precise site of theoriginal treatment; but should occur along the length of the targetnerve.

In some embodiments, repeated treatments may be applied to the targetnerve at 4 week intervals over a 3 month period (or 12 week period), forexample. A total of 3 monthly (or 4 week interval) treatments may occurover the three month period.

In a more aggressive approach, repeated treatments may be applied to thetarget nerve at 1 week intervals over a 3 month period. A total of 12weekly treatments may occur over a 3 month period.

The interval timing may depend on distance to the transection site ofthe nerve from the site of inducing axonotmesis. As the nerveregeneration rate is about 1 mm to 2 mm per day, shorter distancesbetween the site of axonotmesis (initial site or follow-on site) and thetransection site of the nerve may benefit from shorter repeat treatmentintervals so as to maintain a degeneration of the target nerve at thenerve's transection site while longer distances between the axonotmesissite and the transection site may allow for longer intervals. Therepeated interruption of the regeneration of the identified nerve mayinduce chronic denervation of the identified nerve 616.

In some embodiments, the chronic denervation of the nerve reduces aregenerative rate/capacity of the identified nerve 618. After nerveinjury, regeneration-associated genes (RAGs) are up-regulatedtransiently in the neurons while genes associated with normal synaptictransmissions are down-regulated, FIG. 18. Schwann cells in thedegenerated nerve stump undergo proliferation during Walleriandegeneration and express many RAGs. The gene profiles support theoutgrowth of axons, but the expression is short lived such that overtime, the expression of RAGs is down-regulated and the capacity of theinjured neurons to regenerate their axons and Schwann cells to supportregeneration is diminished. Accordingly, in some embodiments of thepresent invention, it may be beneficial to delay regeneration of theidentified nerve until the expression of RAGs is down-regulated and theregenerative rate or capacity of the nerve is sufficiently diminished.As stated above, the regeneration rate of a nerve may be about 1 mm to 2mm per day. In some embodiments, the chronic denervation may reduce aregeneration rate of a nerve to less than 1 mm per day, to less than 0.5mm per day, to less than 0.1 mm per day, less than 0.05 mm per day, orpermanently disrupted by the chronic denervation (i.e., approximately 0mm per day).

Advantageously, the disruption of the regeneration of the nerve afteramputation may prevent the nerve from forming a neuroma at thetransected end of the nerve in the residual stump of the patient 620.Neuromas may result of the normal nerve regrowth during the healingprocess. The lack of an axonal sheath at the residual limb may result ina chaotic pattern of regrowth forming a ball-like intertwined structureat the distal end of the transected nerve. The incidence of painfulneuromas is thought to be between 10 to 25%. Limb pain from neuroma isoften variable in intensity, of intermittent duration, with changeablequalities of aching, cramping or shooting. According to someembodiments, disruption of the regeneration of the nerve afteramputation may prevent the nerve from extending to the residual limb ofthe patient and may thereby avoid the formation of a neuroma at thetransected end of the nerve all together. Thus some embodiments of theinvention may be directed to the prevention of the formation of one ormore neuromas after amputation of an extremity of a patient or aftertransection of a nerve.

For example, FIGS. 19A-19D illustrate an amputation of a hand 704 of apatient 700 with an arm 702 according to method 600. Arm 702 may includea plurality of nerves 705, 706 extending down the length of the arm 702and innervating various portions of the arm 702. An amputation of a hand704 of the arm 702 may be planned and a location of inducing axonotmesismay be based thereon.

After planning the amputation of the hand 704, axonotmesis of nerves705, 706 may be induced at locations 708, 710, respectively. Asexplained above, the inducement of axonotmesis of nerves 705, 706 may becarried out using embodiments of the therapeutic cryoprobes describedabove. Additionally, in many embodiments, the inducement of axonotmesisof nerves 705, 706 may be performed prior to amputation of hand 704. Itis understood however, that in other embodiments, axonotmesis isperformed concurrently with the amputation of hand 704 or shortly afteramputation of hand 704.

As illustrated in FIG. 19A, degeneration of the nerves 705, 706 (dottedlines) occurs distal from the site of inducing axonotmesis 708, 710. Asillustrated in FIG. 19B, after inducing axonotmesis of the targetnerve(s) and amputation of the hand 704, the nerves 705, 706 aredegenerated at the transection sites 712, 714 at the residual limb ofthe patient according to the method 600.

In some embodiments, the method 600 may proceed by interrupting aregeneration process of the one or more transected nerves 705, 706. Forexample, as illustrated in FIG. 19C, a portion 716, 718 of each nerve705, 706 may regenerate distally from the initial locations 708, 710where axonotmesis was induced after a period of time. Nerves of theperipheral nervous system typically regenerate at 1-2 mm per day. Theregeneration process may be interrupted by reinducing axonotmesis atlocations 708, 710 (or at any location proximal to distal ends 720, 722of the nerves 705, 706) at intervals and over a period of time.Preferably, the repeated induction of axonotmesis is performed prior tothe regeneration of the distal ends 720, 722 of the nerves 705, 706 tothe transected site 712, 714. As the distance between the location 710and transected site 714 is shorter than a distance between location 708and transected site 712, nerve 706 may benefit from a shorter repeattreatment interval compared to a repeat treatment interval of nerve 705.Thus, the interval for repeat treatments may be elected based on adistance between the site of inducing axonotmesis (initial or follow-on)and the site of transection where shorter intervals are preferred forshorter distances and longer intervals are allowed for longer distances.

After a number of interruptions of the regeneration of nerves 705, 706over a period of time, chronic denervation may occur and a regenerationrate of the nerves 705, 706 may be reduced (e.g., reduced to less than 1mm per day, less than 0.5 mm per day, less than 0.25 mm per day, orpermanently deactivated). For example, FIG. 19D illustrates nerves 705,706 after chronic denervation where the nerves 705, 706 effectively donot regenerate toward the distal end of the arm 702. Advantageously,such a method may prevent the nerves 705, 706 from forming a neuroma atthe transected ends 712, 714 of nerves 705, 706.

While the method described above is in the context of amputation, itshould be understood that this is only used as one example of such aplanned surgical intervention that may involve nerve transection orinjury. Embodiments of the invention are not limit to amputation alone.Embodiments of the present invention may be applied to any medicalintervention where nerve transection or injury may result and themethods and device described herein may be used proximal to the point oftransection or injury to avoid (or reduce) the formation of a neuroma.

FIGS. 20A-20B illustrate a distal end of an exemplary cryoprobe 800 fortreating a nerve according to some embodiments. The probe 800 may have aneedle 805 extending distally that is configured to generate a cryozone810. In some embodiments, as illustrated in the close up of needle 805in FIG. 20B, the needle 805 may include one or more marks along thelength of the needle. The one or more marks may comprise a mark 815 formarking a distal end of the cryozone 810 that is generated by the probe800, a mark 820 for marking a proximal end of the cryozone 810 that isgenerated by the probe 800, and/or a mark 825 for marking a center of athe cryozone 810 that is generated by the probe 800.

The marks 815, 820, 825 may be utilized for visually aligning the needle805 of a probe 800 with a target nerve. For example, FIG. 21 illustratesan exemplary method 900 of treating a nerve according to someembodiments. At step 902, a needle of the cryotherapy probe ispositioned across the target nerve. The one or more markings indicativeof a treatment area (e.g., marks 815, 820, 825) of the needle may bealigned with the nerve 904. After alignment, the cryotherapy probe maybe activated to deliver the cooling therapy 906.

In some embodiments, the needle may be provided with an echogeniccoating that makes the needle more visible under ultrasound imaging. Forexample, in some embodiments, the entire length of the needle may beprovided with an echogenic coating. Alternatively, the one or more ofthe marks 815, 820, 825, may be provided with an echogenic coating suchthat the distal end, proximal end, or center of the cryozone associatedwith the needle is visible under ultrasound imaging. In otherembodiments, the one or more marks may be provided by a lack ofechogenic coating. For example, in some embodiments, the length of theneedle may be provided with an echogenic coating except for at the oneor more marks 815, 820, 825, such that when viewed under ultrasoundguidance, the distal, proximal, or center of the cryozone would beassociated with the portion of the needle without the echogenic coating.Alternatively, the length of the needle may be provided with theechogenic coating that ceases at the center of the associated cryozone,such that when viewed under ultrasound guidance, the distal end of theechogenic coating would be associated with a center of a cryozone of theneedle.

Long needles may be used in some embodiments (e.g., 8-15 mm, 20 mm, 90mm etc.). Longer needles may require a smaller gauge (larger diameter)needle so they have sufficient rigidity to maintain consistent spacingwhen placed deep in the tissue, but not so large as to createsignificant mechanical injury to the skin and tissue when inserted(e.g., greater than 20 ga). Alternate configurations of the device mayhave two or more needles spaced generally 3-5 mm apart of lengthsranging from up to 20 mm or greater, typically of 25 gauge or 23 gauge.Single needle configurations may be even longer (e.g., 90 mm) forreaching target tissues that are even deeper (e.g., >15 mm or so belowthe dermis). Longer needle devices (e.g., >10 mm) may not need activeheating of the skin warmer and/or cladding found in designs usingshorter needle(s) as the cooling zone may be placed sufficiently deepbelow the dermis to prevent injury. In some embodiments, devices withsingle long needle configurations may benefit from active nerve locationsuch as ultrasound or electrical nerve stimulation to guide placement ofthe needle. Further, larger targets may require treatment from bothsides to make sure that the cold zone created by the needle fully coversthe target. Adjacent treatments placing the needle to either side of anerve during two successive treatment cycles may still provide aneffective treatment of the entire nerve cross-section.

In some situations, a probe with multiple spaced apart needles may bepreferable (e.g., 2, 3, 4 or more). A device employing multiple needlesmay decrease the total treatment duration by creating larger coolingzones. Further, a multi-needle device may be configured to providecontinuous cooling zones between the spaced apart needles. In someembodiments, the needles may be spaced apart by 1-5 mm. The spacing maybe dependent on the type of tissue being targeted. For example, whentargeting a nerve, it may be preferable to position the nerve betweenthe two or more needles so that cooling zones are generated on bothsides of the nerve. Treating the nerve from both sides may increase theprobability that the entire cross-section of the nerve will be treated.For superficial peripheral nerves, the nerves may be at depths rangingfrom 2-6 mm and may be smaller in diameter, typically <2 mm.Accordingly, devices for treating superficial peripheral nerves maycomprises two or more 27 gauge needles spaced <2 mm apart and havingtypical lengths less than 7 mm (e.g., 6.9 mm); however longer needlesmay be required to treat the full patient population in order to accesspatients with altered nerve anatomy or patients with higher amounts ofsubcutaneous tissue such as those with high BMIs.

A treatment cycle may comprise a 10 second pre-warm phase, followed by a60 second cooling phase, followed thereafter by a 15 second post-warmphase with 40° C. skin warmer throughout. It should be understood thatother treatment cycles may be implemented. In some embodiments, apre-warming cycle can range from 0 to up to 30 seconds, preferably 5-15seconds sufficient to pre-warm the cryoprobe and opposing skin.Treatment cooling may range from 5-120 seconds, preferably 15-60 secondsbased on the flow rate, geometry of the cryoprobe, size of the therapyzone, size of the target nerve or tissue and the mechanism of actiondesired. Post warming can range from 0-60 seconds, preferably 10-15seconds sufficient to return the cryoprobe to a steady state thermalcondition and possibly to free the cryoprobe needle(s) from the frozentherapy zone (e.g., at least 0° C.) prior to removing the cryoprobeneedles. For example, in some embodiments, devices with 6.9 mm longcladded needles may be warmed with a 30° C. heater. The treatment cyclemay comprise a 10 second pre-warm phase, a 35 second cooling phase, anda 15 second post-warm phase. Advantageously, such a treatment cycle maymake an equivalent cryozone as the treatment cycle used in the study ina shorter amount of time (e.g., a 35 second cooling phase compared to a60 second cooling phase).

In some embodiments, treatment devices and treatment cycles may beconfigured to deliver a preferred cryozone volume. For example, in someembodiments, devices and treatment cycles may be configured to generatecryozones (defined by the 0 degree isotherm) having a cross-sectionalarea of approximately 14-55 mm² (e.g., 27 mm²). Optionally, the devicesand treatment cycles may be configured to generate cryozones having avolume of approximately 65-125 mm³ (e.g., 85 mm³).

Accordingly, in some embodiments, treatment cycles may be configuredwith cooling phases ranging between 15-75 seconds (e.g., 30 seconds, 35seconds, 40 seconds, 45 seconds, etc.) depending on cooling fluid flowrates, warming phase durations, warming phase temperature, number ofcooling needles, needle spacing, or the like in order to generate adesired cryozone. Similarly, treatment cycles may be configured withwarming phases operating a temperatures ranging between 10-45° C.depending on the length of cooling phases, number of needles, needlespacing, etc. in order to generate a desired cryozone. Generally, withhigher degree warming phases, the duration of the pre-warm phase and thecooling phase will be longer, however the post-warm phase duration maybe reduced. In some embodiments the temperature can be set to onetemperature during the pre-warm phase, another temperature during thecooling phase, and a third temperature during the post-warm phase.

In some embodiments, devices may be configured to limit flow rate of acooling fluid to approximately 0.34-0.80 SLPM (gas phase). Optionally,in some embodiments, it may be preferable to configure the device andthe treatment cycle to maintain the tip a less than −55° C. duringcooling phases. In some embodiments, it may be preferable to configurethe device and the treatment cycle to have the tip return to at least 0°C. at the end of the post-warm phase so as to ensure the device may besafely removed from the tissue after the treatment cycle.

While generally describing treatment cycles as includingpre-heating/warming phases, it should be understood that other treatmentcycles may not require a pre-heating/warming phase. For example, largerneedle devices (e.g., 30-90 mm) may not require a pre-heat/warm phase.Larger needles may rely on the body's natural heat to bring the needleto a desired temperature prior to a cooling phase.

In some embodiments of the present invention, treatment guidance canrely on rigid or boney landmarks because they are less dependent uponnatural variations in body size or type, e.g. BMI. Soft tissues,vasculature and peripheral nerves pass adjacent to the rigid landmarksbecause they require protection and support. The target nerve to relievepain can be identified based on the diagnosis along with patientsidentifying the area of pain, biomechanical movements that evoke painfrom specific areas, palpation, and diagnostic nerve blocks using antemporary analgesic (e.g. 1-2% Lidocaine). Target nerve (tissue) can belocated by relying on anatomical landmarks to indicate the anatomicalarea through which the target nerve (tissue) reside. Alternatively,nerve or tissue locating technologies can be used. In the case ofperipheral nerves, electrical stimulation or ultrasound can be used tolocate target nerves for treatment. Electrical nerve stimulation canidentify the nerve upon stimulation and either innervated muscle twitchin the case of a motor nerve or altered sensation in a specific area inthe case of a sensory nerve. Ultrasound is used to visualize the nerveand structures closely associated with the nerve (e.g. vessels) toassist in placing the cryoprobe in close proximity to the target nerve.By positioning the patient's skeletal structure in a predeterminedposition (e.g. knee bent 30 degrees or fully extended), one can reliablyposition the bones, ligaments, cartilage, muscle, soft tissues(including fascia), vasculature, and peripheral nerves. Externalpalpation can then be used to locate the skeletal structure and therebylocate the pathway and relative depth of a peripheral nerve targeted fortreatment.

A treatment of peripheral nerve tissue to at least −20° C. for greaterthan 10 seconds (e.g., at least 20 seconds preferably) may be sufficientto trigger 2nd degree Wallerian degeneration of the axon and mylinatedsheath. Conduction along the nerve fibers is stopped immediatelyfollowing treatment. This provides immediate feedback as to the locationof the target peripheral nerve or associated branches when theassociated motion or sensation is modified. This can be used to refinerigid landmark guidance of future treatments or to determine whetheraddition treatment is warranted.

By using rigid landmarks, one may be able to direct the treatmentpattern to specific anatomical sites where the peripheral nerve islocated with the highest likelihood. Feedback from the patientimmediately after each treatment may verify the location of the targetperipheral nerve and its associated branches. Thus, it should beunderstood that in some embodiments, the use of an electronic nervestimulation device to discover nerve location is not needed or used,since well-developed treatment zones can locate target nerves. This maybe advantageous, due the cost and complexity of electronic nervestimulation devices, which are also not always readily available.

In alternative embodiments of the invention, one could use an electronicnerve stimulation device (either transcutaneous or percutaneous) tostimulate the target peripheral nerve and its branches. Withtranscutaneous electric nerve stimulation (TENS) the pathway of thenerve branch can be mapped in an X-Y coordinates coincident with theskin surface. The Z coordinate corresponding to depth normal to the skinsurface can be inferred by the sensitivity setting of the electricalstimulation unit. For example, a setting of 3.25 mA and pulse durationof 0.1 ms may reliably stimulate the frontal branch of the temporalnerve when it is within 7 mm of the skin surface. If a higher currentsetting or longer pulse duration is required to stimulate the nerve,then the depth may be >7 mm. A percutaneous electrical nerve stimulator(PENS) can also be used to locate a target peripheral nerve. Based onrigid anatomical landmarks, a PENS needle can be introduced through thedermis and advanced into the soft tissues. Periodic stimulating pulsesat a rate of 1-3 Hz may be used to stimulate nerves within a knowndistance from the PENS needle. When the target nerve is stimulated, thesensitivity of the PENS can be reduced (e.g. lowering the currentsetting or pulse duration) narrowing the range of stimulation. When thenerve is stimulated again, now within a smaller distance, the PENSsensitivity can be reduced further until the nerve stimulation distanceis within the therapy zone dimensions. At this point, the PENS needlecan be replaced with the focused cold therapy needle(s) and a treatmentcan be delivered. The PENS and focused cold therapy needles can beintroduced by themselves or through a second larger gage needle orcannula. This may provide a rigid and reproducible path when introducinga needle and when replacing one needle instrument with another. A rigidpathway may guide the needle to the same location by preventing needletip deflection, which could lead to a misplaced therapy and lack ofefficacy.

While many of the examples disclosed herein related to puncturing theskin in a transverse manner to arrive at a target nerve, othertechniques can be used to guide a device to a target nerve. For example,insertion of devices can be made parallel to the surface of the skin,such that the (blunted) tip of the device glides along a particularfascia to arrive at a target sensory nerve. Such techniques and devicesare disclosed in U.S. Pub. No. 2012/0089211, the entirety of which isincorporated by reference. Possible advantages may include a singleinsertion site, and guidance of a blunt tip along a layer common withthe path or depth of the target nerve. This technique may be aposition-treatment—thaw, reposition treatment, thaw, etc.

One or more computing devices may be adapted to provide desiredfunctionality by accessing software instructions rendered in acomputer-readable form. When software is used, any suitable programming,scripting, or other type of language or combinations of languages may beused to implement the teachings contained herein. However, software neednot be used exclusively, or at all. For example, some embodiments of themethods and systems set forth herein may also be implemented byhard-wired logic or other circuitry, including but not limited toapplication-specific circuits. Combinations of computer-executedsoftware and hard-wired logic or other circuitry may be suitable aswell.

Embodiments of the methods disclosed herein may be executed by one ormore suitable computing devices. Such system(s) may comprise one or morecomputing devices adapted to perform one or more embodiments of themethods disclosed herein. As noted above, such devices may access one ormore computer-readable media that embody computer-readable instructionswhich, when executed by at least one computer, cause the at least onecomputer to implement one or more embodiments of the methods of thepresent subject matter. Additionally or alternatively, the computingdevice(s) may comprise circuitry that renders the device(s) operative toimplement one or more of the methods of the present subject matter.

Any suitable computer-readable medium or media may be used to implementor practice the presently-disclosed subject matter, including but notlimited to, diskettes, drives, and other magnetic-based storage media,optical storage media, including disks (e.g., CD-ROMS, DVD-ROMS,variants thereof, etc.), flash, RAM, ROM, and other memory devices, andthe like.

The subject matter of embodiments of the present invention is describedhere with specificity, but this description is not necessarily intendedto limit the scope of the claims. The claimed subject matter may beembodied in other ways, may include different elements or steps, and maybe used in conjunction with other existing or future technologies. Thisdescription should not be interpreted as implying any particular orderor arrangement among or between various steps or elements except whenthe order of individual steps or arrangement of elements is explicitlydescribed.

Different arrangements of the components depicted in the drawings ordescribed above, as well as components and steps not shown or describedare possible. Similarly, some features and sub-combinations are usefuland may be employed without reference to other features andsub-combinations. Embodiments of the invention have been described forillustrative and not restrictive purposes, and alternative embodimentswill become apparent to readers of this patent. Accordingly, the presentinvention is not limited to the embodiments described above or depictedin the drawings, and various embodiments and modifications may be madewithout departing from the scope of the claims below.

What is claimed is:
 1. A prophylactic method of preventing neuromaformation in nerve tissue associated with transection of a nerve duringa medical intervention, the method comprising: identifying a nerveextending across a transection path which separates a distal portion ofthe nerve from a proximal portion of the nerve; and administering aprophylactic cooling therapy to the identified nerve at a locationproximal to the transection path so as to degenerate the identifiednerve across the transection path prior to a surgical transection alongthe transection path, wherein administering the cooling therapy prior tothe surgical transection prevents or reduces neuroma formation at atransected end of the identified nerve after transection of the nerve.2. The method of claim 1, further comprising administering a repeatedapplication of cooling therapy targeting a regeneration of theidentified nerve at one or more locations along a length of theidentified nerve and proximal to the regeneration of the nerve extendingtoward a location of the transection of the identified nerve.
 3. Themethod of claim 2, wherein the repeated application of cooling therapyreduces a regenerative rate of the identified nerve to less than 1 mmper day.
 4. The method of claim 3, wherein the regenerative rate of theidentified nerve is reduced to less than 0.5 mm per day.
 5. The methodof claim 1, wherein administering the cooling therapy to the identifiednerve comprises: positioning a needle of a cryotherapy probe across theidentified nerve; aligning one or more visual indicia of the needle ofthe cryotherapy probe with the nerve, the visual indicia beingindicative of a treatment area along a length of the needle; andactivating the cryotherapy probe to deliver the cooling therapy.
 6. Themethod of claim 5, wherein the visual indicia comprise a markeridentifying a distal end of the treatment area along the length of theneedle.
 7. The method of claim 5, wherein the visual indicia comprise amarker identifying a proximal end of the treatment area along the lengthof the needle.
 8. The method of claim 5, wherein the visual indiciacomprise a marker identifying a center of the treatment area along thelength of the needle.
 9. The method of claim 1, wherein administeringthe cooling therapy to the nerve comprises: positioning a needle of acryotherapy probe along a length of the identified nerve and activatingthe cryotherapy probe to deliver the cooling therapy.
 10. The method ofclaim 1, wherein the surgical transection separates a body extremityfrom a body of a patient to effect a surgical amputation.
 11. The methodof claim 10, wherein the surgical amputation is performed afterdegeneration of the identified nerve across the transection path. 12.The method of claim 1, further comprising administering a repeatedapplication of cooling therapy targeting a regeneration of theidentified nerve at one or more locations along a length of theidentified nerve, wherein the repeated application of cooling therapy isadministered over a period of one month to three months before thetransection of the nerve.
 13. The method of claim 1, further comprisingadministering a repeated application of cooling therapy targeting aregeneration of the identified nerve at one or more locations along alength of the identified nerve, wherein the repeated application ofcooling therapy is applied between a daily interval and a four weekinterval.
 14. A method of transecting a nerve extending to a targettissue, the method comprising: degenerating a portion of the nerve byperforming a prophylactic treatment on the nerve at a treatment locationalong the nerve, wherein the treatment degenerates an axon of the nervedistal to the treatment location while preserving a connective tissueframework of the nerve; after the prophylactic treatment, transectingthe preserved connective tissue framework of the nerve at a transectionlocation distal to the treatment location; and repeatedly disrupting aregeneration of the nerve for a period of time so as to induce chronicdenervation of the nerve, wherein the chronic denervation of the nervereduces a regenerative rate of the nerve and delays neuroma formation atthe transection location of the nerve.
 15. The method of claim 14,wherein repeatedly disrupting the regeneration of the nerve comprisesrepeatedly applying cooling therapy to the nerve at a location proximalto the target tissue.
 16. The method of claim 15, wherein the repeatedapplication of cooling therapy is administered over a period of onemonth to three months before the transection.
 17. The method of claim15, wherein the repeated application of cooling therapy is appliedbetween a daily interval and a four week interval.
 18. The method ofclaim 15, wherein the cooling therapy comprises: positioning a needle ofa cryotherapy probe across the nerve; aligning visual indicia of theneedle of the cryotherapy probe with the nerve, the visual indicia beingindicative of a treatment area along a length of the needle; andactivating the cryotherapy probe to deliver the cooling therapy.
 19. Themethod of claim 14, wherein treating the nerve at the treatment locationalong the nerve while preserving a connective tissue framework of thenerve comprises applying thermal ablation therapy with a radiofrequency,ultrasound, microwave, or laser treatment of the nerve.
 20. The methodof claim 14, wherein treating the nerve at the treatment location alongthe nerve while preserving a connective tissue framework of the nervecomprises applying a cooling therapy using a cryogenic cooling device.21. The method of claim 14, wherein the preserved connective tissueframework of the nerve is transected with a surgical amputation of abody extremity of a patient.